Targeted High-Throughput Sequencing of 220 genes identifies a high proportion of causative mutations in over 80 patients with undiagnosed intellectual disability. C. Redin1, 2, S. Le Gras3, J. Lauer4, A. Creppy1, 4, Y. Herenger4, V. Geoffroy3, Y. Alembik5, M. Doco-Fenzy6, B. Doray5, P. Edery7, S. El Chehadeh8, L. Faivre8, 9, E. Flori10, B. Isidor11, G. Lesca7, A. Masurel8, B. Jost3, J. Muller1, 4, B. Gérard4, J. L. Mandel1, 2, 4, A. Piton1, 2 1) Translational medicine & Neurogenetics, IGBMC, Illkirch, France; 2) Chaire de Génétique Humaine, Collège de France; 3) Microarray and Sequencing Platform, IGBMC, Illkirch, France; 4) Laboratoire de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, France; 5) Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; 6) Biology Section, Department of Genetics, University Hospital of Reims, Reims, France; 7) Laboratoire de Cytogénétique Constitutionnelle, Service de Génétique, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, Bron, France; 8) Centre de génétique et Centre de Référence Anomalies du développement et Syndromes malformatifs, Hôpital d'Enfants, CHU Dijon, Dijon, France; 9) Génétique des anomalies du développement (GAD) EA 4271, Faculté de Médecine, Université de Bourgogne, Dijon, France; 10) Service de cytogénétique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France; 11) Service de Génétique Médicale, Centre Hospitalier Universitaire de Nantes 7, Quai Moncousu, 44000 Nantes Cedex, France.

   Over 200 genes have a well-documented implication in monogenic forms of intellectual disability (ID), of which about 100 are located on the X-chromosome. While there is a good coverage for diagnostic demands in patients with evocative syndromic forms, for lesser syndromic patients the diagnostic offer is limited to Fragile-X testing and CGH-array analysis and most cases hence remain undiagnosed. We tested a targeted exon-capture approach of 220 ID genes (100 XLID genes and 120 autosomal genes mostly associated to dominant forms) coupled with NGS. We successfully analyzed 82 patients (mostly males and simplex cases) with undiagnosed ID. We identified 15 causative mutations: 9 maternally-inherited or de novo in X-linked genes (DMD, KDM5C, MAOA, MECP2, SLC9A6, FMR1, IQSEC2, IL1RAPL1, SHROOM4) and 6 de novo truncating in autosomal genes (RAI1, SLC2A1, two in DYRK1A, two in TCF4). We also detected 5 likely-causative mutations requiring additional validation analyses. Some causative mutations were rather surprising either by the nature of the mutation itself or when considering the patients phenotype. As examples, we depicted a distal frameshift in DMD in a patient with no muscular phenotype; an extremely complex rearrangement in MECP2 in an 11 years-old boy with severe ID and speech absence; a deletion of FMR1 last exon in a severely affected male with previous extensive molecular investigation; de novo nonsenses in RAI1 and TCF4 in patients without phenotypic traits evocative of Smith-Magenis or Pitt-Hopkins syndromes. Other findings allow supporting previously proposed ID genes such as MAOA, with the first replication of its involvement in ID along with prominent behavioral disturbances (Brunner et al., 1993). Lastly, we report 2 de novo truncating mutations in DYRK1A, in patients with phenotype concordant with previous ones, delineating a peculiar syndrome with microcephaly, speech absence and feeding disorder. The identification of certainly/likely causative mutations in 18-24% of the patients proves the relevance of our strategy for the diagnosis of ID, being more cost-effective than trio-exome sequencing while leading to a comparable proportion of diagnostic results (21-41% in 151 trios, de Ligt,2012 and Rauch, 2012). Finally, the identification of causative mutations in syndromic genes in patients deviating from the typical phenotype expand the clinical spectrum associated with such genes and suggest they should be screened more systematically.

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